ARTHRITIS & RHEUMATISM

Vol. 62, No. 4, April 2010, pp 929–939

DOI 10.1002/art.27334
© 2010, American College of Rheumatology

LY2439821, a Humanized Anti–Interleukin-17 Monoclonal

Antibody, in the Treatment of Patients With
Rheumatoid Arthritis

A Phase I Randomized, Double-Blind, Placebo-Controlled,

Proof-of-Concept Study

M. C. Genovese,1 F. Van den Bosch,2 S. A. Roberson,3 S. Bojin,4 I. M. Biagini,5 Peter Ryan,6

and J. Sloan-Lancaster3

Objective. We undertook this study to evaluate
safety, tolerability, pharmacokinetics, pharmacodynam-
ics, and efficacy of LY2439821, a humanized anti–
interleukin-17 (anti–IL-17) monoclonal antibody, in a
first in-human trial in rheumatoid arthritis (RA) pa-
tients taking oral disease-modifying antirheumatic
drugs (DMARDs).
Methods. This randomized, double-blind, placebo-
controlled study consisted of 2 parts. In part A, 20
patients received 1 intravenous (IV) dose of LY2439821
(0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo
followed by 8 weeks of evaluation. End points included
safety, tolerability, and pharmacokinetics. In part B, 77
patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0
mg/kg) or placebo every 2 weeks for a total of 5 doses,
Supported by Chorus, a Division of Eli Lilly.
1
M. C. Genovese, MD: Stanford University, Palo Alto, Cali-
2
fornia; F. Van den Bosch, MD, PhD: University Hospital Ghent,
Ghent, Belgium; 3S. A. Roberson, BSPH, J. Sloan-Lancaster, PhD:
Chorus, Eli Lilly, Indianapolis, Indiana; 4S. Bojin, PhD: County
Emergency Hospital of St. Gheorghe, Covasna, Romania; 5I. M.
Biagini, MD: Bacau County Emergency Hospital, Bacau, Romania;
6
Peter Ryan, MB, BS, FRACP: Nucleus Network, Melbourne, Victo-
ria, Australia.
Dr. Genovese has received consulting fees from Eli Lilly,
Novartis, Schering-Plough, and Amgen (less than $10,000 each). Ms
Roberson owns stock or stock options in Eli Lilly. Dr. Ryan has
received speaking fees from Eli Lilly (less than $10,000 each). Dr.
Sloan-Lancaster owns stock or stock options in Eli Lilly and has
received patents and has patent applications pending for compounds
that are not related to this study.
Address correspondence and reprint requests to M. C.
Genovese, MD, Stanford University, 1000 Welch Road, Suite 203,
Palo Alto, CA 94304. E-mail: genovese@stanford.edu.
Submitted for publication October 9, 2009; accepted in re-
vised form December 28, 2009.
929
with a total evaluation period of 16 weeks. End points
included safety, tolerability, pharmacokinetics/
pharmacodynamics, and efficacy (Disease Activity Score
in 28 joints [DAS28] and percentages of patients meet-
ing American College of Rheumatology 20%, 50%, or
70% improvement criteria [achieving an ACR20,
ACR50, or ACR70 response]). The primary efficacy end
point was the DAS28 at week 10.
Results. Baseline characteristics were similar
across all groups. Changes in the DAS28 were signifi-
cantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-
LY2439821–combined groups (ⴚ2.3, ⴚ2.4, and ⴚ2.3,
respectively) than in the placebo group (ⴚ1.7) at week
10 (P < 0.05), and these differences were significant as
early as week 1. Percentages of ACR20, ACR50, and
ACR70 responses as well as improvements in the ACR
core set of measures were greater in LY2439821-treated
patients than in placebo-treated patients at multiple
time points. There was no apparent dose-response rela-
tionship in treatment-emergent adverse events.
Conclusion. LY2439821 added to oral DMARDs
improved signs and symptoms of RA, with no strong
adverse safety signal noted. This first evaluation of
LY2439821 supports neutralization of IL-17 as a poten-
tial novel goal for the treatment of RA.
The treatment of rheumatoid arthritis (RA) has
traditionally included corticosteroids and conventional
disease-modifying antirheumatic drugs (DMARDs).
While these therapies provide some benefit, their effi-
cacy has been limited. Newer, biologically-based thera-
pies include molecules that inhibit cytokine activity
930
(tumor necrosis factor [TNF] inhibitors, interleukin-1
receptor antagonist [IL-1Ra], or anti–IL-6R monoclonal
antibody), block T cell–mediated costimulation (CTLA-
4Ig), or modify B cell biology (anti-CD20) (1–3). These
therapies have been effective in moderate-to-severe RA
and have slowed disease progression, as determined
radiographically, particularly when combined with meth-
otrexate (MTX). However, less than two-thirds of the
patients treated in pivotal trials meet at least the Amer-
ican College of Rheumatology 50% improvement crite-
ria (achieve at least an ACR50 response) (4), and
disease remission (a Disease Activity Score in 28 joints
[DAS28] ⬍2.6 [5]) is achieved by only a small minority
of these patients (3,6–9).
IL-17 (or IL-17A) is a proinflammatory cytokine
produced primarily by a subset of CD4⫹ T cells, called
Th17 cells, which represent a third subset of CD4⫹
“helper” lymphocytes in addition to the classically de-
scribed Th1 and Th2 populations (10,11). Th17 cells
likely evolved to provide adequate immunity to specific
classes of pathogens, such as extracellular bacteria and
fungi, through the role of IL-17 in the generation and
recruitment of neutrophils (12–14). However, aberrant
Th17 responses and IL-17 production have been impli-
cated in a variety of autoimmune diseases, including RA
(15,16).
IL-17 could contribute to the pathogenesis of RA
in several ways, some in synergy with TNF␣ and/or IL-1␤
and others independently of these 2 cytokines. Under
normal conditions, levels of IL-17 are extremely low or
undetectable in human sera; however, 2 studies have
shown elevated levels in sera and synovial fluid in a
subset of patients with RA (17,18). Additionally,
Chabaud et al demonstrated that RA synovial tissue
explants produce biologically active IL-17 in addition to
IL-6, TNF, and IL-1␤ (19). Immunohistochemical stain-
ing of RA synovium has identified a subset of infiltrating
T cells expressing IL-17 (19,20).
In preclinical studies, IL-17 has been shown to
contribute to joint inflammation and destruction, as well
as to bone erosion, and these activities are, in part,
independent of IL-1␤. Additionally, blockade of IL-17
by antibody or soluble receptors reduces inflammation
and bone erosion in various animal arthritis models (21).
Thus, blocking the biologic activity of IL-17 is predicted
to be beneficial in the treatment of RA, potentially re-
ducing joint inflammation and preventing bone erosion.
LY2439821 is a humanized monoclonal antibody
(IgG4) that binds to and neutralizes the biologic effects
of IL-17. It is highly specific to IL-17, with no binding to
other IL-17 family members (unpublished data). Based
GENOVESE ET AL
on the above-described data, blocking IL-17 is predicted
to be beneficial in the treatment of RA and other
autoimmune diseases.
This study is the first evaluation of the tolerabil-
ity, pharmacokinetics, and pharmacodynamics of
LY2439821 in humans, and was a combined single/
multiple dose administration, randomized, double-blind,
placebo-controlled, phase I study in RA patients taking
background oral DMARDs. Tolerability and pharmaco-
kinetics were evaluated after a single escalating dose in
part A, and tolerability, pharmacokinetics, pharmaco-
dynamics, and efficacy were evaluated after multiple
dosing in part B.
PATIENTS AND METHODS
Patients. Patients enrolled were ages 18–75 years and
were diagnosed as having RA according to the 1987 revised
criteria of the ACR (formerly, the American Rheumatism
Association) (22) with a global functional class of I, II, or III
according to the ACR 1991 revised criteria (23). Inclusion
criteria included weight of 40–86 kg (inclusive) and the stable
use of ⱖ1 DMARDs for a minimum of 4 weeks prior to the
study (MTX 7.5–25 mg/week, hydroxychloroquine [HCQ]
ⱕ400 mg/day, sulfasalazine [SSZ] 1,000–3,000 mg/day, lef-
lunomide 5–20 mg/day, or azathioprine ⱕ150 mg/day or
2 mg/kg/day). Combinations of MTX, HCQ, and/or SSZ were
allowed. Females of childbearing potential used appropriate
contraception, as defined in the protocol. Additionally, pa-
tients entering part B of the study must have experienced an
insufficient response to at least 1, but not more than 5, oral
DMARDs and must have had ⱖ6 tender joints and ⱖ6 swollen
joints (28-joint assessment) as well as either C-reactive protein
⬎1.5 mg/dl or erythrocyte sedimentation rate ⱖ28 mm/hour at
the time of screening for the study.
Primary exclusion criteria included the use of ritux-
imab within 6 months, abatacept within 3 months, infliximab,
adalimumab, cyclosporine, or mycophenolic acid within 2
months, and etanercept or anakinra within 28 days prior to
study randomization. Evidence of any active or recent infec-
tions, or a history of malignancy or other autoimmune disease,
were also exclusion criteria. Patients in part B were also
excluded if the use of etanercept, adalimumab, infliximab,
anakinra, or abatacept was discontinued for lack of efficacy.
Patients could participate in only one part of the study.
Study design. This was a randomized, double-blind,
placebo-controlled study of LY2439821 conducted at 17 sites
in Australia, Belgium, and Romania between November 2006
and February 2008. LY2439821 and placebo were adminis-
tered by intravenous infusion (1 hour). Randomization during
part A was performed manually by a study drug coordinator,
and part B used an interactive voice response system for
randomization. All study personnel remained blinded to treat-
ment until study completion. The dose levels of LY2439821
administered in the study were determined based on the results
of previous preclinical studies (unpublished data).
In part A, patients were given a single escalating
intravenous (IV) dose of LY2439821 or placebo (5 patients per
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 931

Table 1. Demographic and baseline characteristics of the patients for part A; single dose escalation*
LY2439821

Placebo 0.06 mg/kg 0.2 mg/kg 0.6 mg/kg 2.0 mg/kg

(n ⫽ 4) (n ⫽ 4) (n ⫽ 4) (n ⫽ 4) (n ⫽ 4) P†
Age, years 41.3 ⫾ 13.8 65.3 ⫾ 7.8 51.7 ⫾ 13.0 51.1 ⫾ 14.2 49.3 ⫾ 9.7 0.069‡
Weight, kg 75.5 ⫾ 11.0 72.3 ⫾ 12.8 70.3 ⫾ 12.3 74.3 ⫾ 11.8 64.5 ⫾ 5.5 0.606‡
BMI, kg/m2 27.8 ⫾ 3.4 27.2 ⫾ 5.2 25.6 ⫾ 6.0 27.6 ⫾ 4.4 23.9 ⫾ 2.5 0.619‡
No. of men/women 1/3 2/2 2/2 2/2 0/4 0.637§
ACR functional class, no. (%) 0.346¶
I 2 (50.0) 3 (75.0) 2 (50.0) 2 (50.0) 2 (50.0) –
II 0 (0.0) 1 (25.0) 2 (50.0) 2 (50.0) 0 (0.0) –
III 2 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (50.0) –
Disease duration, years 7.7 ⫾ 5.66 22.0 ⫾ 8.02 5.6 ⫾ 3.76 8.0 ⫾ 5.68 6.0 ⫾ 4.60 0.004¶
Glucocorticoid use
Yes, no. (%) 1 (25.0) 4 (100.0) 1 (25.0) 3 (75.0) 1 (25.0) –
Daily dose, mg 50.0# 6.3 ⫾ 2.99 5.0# 10.0 ⫾ 5.00 0.5# ⬍0.001¶
MTX use
Yes, no. (%) 4 (100.0) 4 (100.0) 3 (75.0) 2 (50.0) 4 (100.0) –
Weekly dose, mg 19.4 ⫾ 5.15 12.5 ⫾ 2.89 11.7 ⫾ 2.89 20.0 ⫾ 0.00 19.4 ⫾ 14.77 0.684¶
HCQ use
Yes, no. (%) 2 (50.0) 0 (0.0) 2 (50.0) 0 (0.0) 0 (0.0) –
Daily dose, mg 300.0 ⫾ 141.4 – 200.00 ⫾ 0.00 – – ⬍0.001
Leflunomide use
Yes, no. (%) 0 (0.0) 1 (25.0) 0 (0.0) 2 (50.0) 0 (0.0) –
Daily dose, mg – 20.0# – 20.0 ⫾ 0.00 – –
Concomitant DMARD use,
no. (%)
One DMARD 1 (25.0) 3 (75.0) 3 (75.0) 4 (100.0) 4 (100.0) –
Two DMARDs 2 (50.0) 1 (25.0) 1 (25.0) 0 (0.0) 0 (0.0) –
Three DMARDs 1 (25.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) –

* Except where indicated otherwise, values are the mean ⫾ SD. BMI ⫽ body mass index; ACR ⫽ American College of Rheumatology; MTX ⫽
methotrexate; HCQ ⫽ hydroxychloroquine; DMARD ⫽ disease-modifying antirheumatic drug.
† P values are for overall comparison, and nonsignificance indicates randomization was done appropriately for demographic categories (age, sex,
etc.).
‡ By analysis of variance with treatment and center as fixed factors.
§ By Fisher’s exact test.
¶ By analysis of covariance with treatment and center as fixed effects for continuous variables and by Fisher’s exact test for categorical variables.
# Unable to estimate SD or SD not calculated.

dose level; 1 randomized to placebo and 4 randomized to
LY2439821 at 0.06, 0.2, 0.6, or 2.0 mg/kg). Escalation to the
next LY2439821 dose level required acceptable safety data
from all patients in the previous cohort through 24 hours
postdosing and from at least 2 LY2439821-treated patients
through 1 week postdosing. In order to maintain the blind,
safety data through 1 week postdosing for the first 3 dosed
patients were required prior to each safety review. Safety data
from all patients in part A through a minimum of 3 weeks
postdosing were reviewed by a formally constituted internal
safety assessment committee prior to the commencement of
part B. Primary end points included safety and tolerability.
Pharmacokinetic parameters after a single dose were also
evaluated.
Patients (total of 77) in part B were assigned by
parallel randomization to treatment with placebo or with 0.2,
0.6, or 2.0 mg/kg LY2439821 administered IV every 2 weeks
for a total of 5 treatments. Patients were then followed up for
an additional 8 weeks after the final infusion. Primary end
points included safety and the DAS28 at week 10. Secondary
end points included percentages of patients achieving ACR20,
ACR50, and ACR70 responses as well as improvements in the
ACR core set of measures (24) (swollen joint count, tender
joint count, patient’s assessment of pain, patient’s and physi-
cian’s global assessments of disease activity, Health Assess-
ment Questionnaire disability index [HAQ DI] score [25], and
levels of acute-phase reactants) at various time points. Phar-
macokinetic parameters were also assessed.
Regulatory and Ethical Review Board approvals from
competent authorities in each country were obtained for the
study protocol. All patients signed an informed consent docu-
ment, and the study was conducted in accordance with the
Declaration of Helsinki and following Good Clinical Practice
guidelines.
Statistical analysis. Baseline values were compared
using an analysis of variance model. Covariates taken into
consideration included treatment and center. For numeric
continuous efficacy measures in part B, an analysis of covari-
ance (ANCOVA) model was used that included treatment and
center as fixed effects and the baseline measurement as a
covariate. Pairwise comparisons between each dose and pla-
cebo were made using the ANCOVA model. For categorical
efficacy response measures, a 2-sided Cochran-Mantel-
Haenszel test was used, adjusted for center between each
932 GENOVESE ET AL

Table 2. Demographic and baseline characteristics of the patients for part B; multiple dose*
LY2439821

Placebo 0.2 mg/kg 0.6 mg/kg 2.0 mg/kg

(n ⫽ 18) (n ⫽ 19) (n ⫽ 20) (n ⫽ 20) P†
Age, years 54.4 ⫾ 9.7 59.6 ⫾ 8.4 57.7 ⫾ 11.5 55.6 ⫾ 8.2 0.464‡
Weight, kg 68.1 ⫾ 12.7 67.3 ⫾ 13.2 67.6 ⫾ 11.5 65.3 ⫾ 11.6 0.882‡
BMI, kg/m2 26.6 ⫾ 4.5 25.4 ⫾ 4.3 27.2 ⫾ 3.9 24.7 ⫾ 4.2 0.272‡
Sex, no. (%) 0.080§
Male 0 (0) 3 (15.8) 1 (5.0) 5 (25.0) –
Female 18 (100) 16 (84.2) 19 (95.0) 15 (75.0) –
ACR functional class, no. (%) 0.211¶
I 3 (16.7) 3 (15.8) 5 (25.0) 1 (5.0) –
II 5 (27.8) 8 (42.1) 5 (25.0) 13 (65.0) –
III 10 (55.6) 8 (42.1) 10 (50.0) 6 (30.0) –
Disease duration, years 6.5 ⫾ 5.67 10.5 ⫾ 13.02 10.9 ⫾ 10.21 6.1 ⫾ 5.48 0.268¶
Swollen joint count, 0–28 12.9 ⫾ 4.18 12.4 ⫾ 5.35 13.7 ⫾ 5.38 11.8 ⫾ 4.95 0.314¶
Tender joint count, 0–28 18.2 ⫾ 4.71 17.3 ⫾ 6.30 16.8 ⫾ 6.34 15.7 ⫾ 7.55 0.458¶
DAS28 6.1 ⫾ 0.74 6.0 ⫾ 0.68 6.0 ⫾ 0.83 5.8 ⫾ 0.86 0.517¶
CRP, mg/dl 2.47 ⫾ 3.21 1.90 ⫾ 2.16 1.80 ⫾ 1.81 2.15 ⫾ 3.01 0.891¶
ESR, mm/hour 64.3 ⫾ 25.24 61.0 ⫾ 26.03 63.6 ⫾ 23.99 69.1 ⫾ 26.26 0.783¶
RF titer, IU/ml 125.2 ⫾ 243.95 69.1 ⫾ 82.13 275.6 ⫾ 597.49 130.1 ⫾ 181.54 0.266¶
HAQ DI score 1.8 ⫾ 0.48 1.7 ⫾ 0.55 1.8 ⫾ 0.66 1.4 ⫾ 0.74 0.065¶
Glucocorticoid use
Yes, no. (%) 6 (33.3) 4 (21.1) 6 (30.0) 8 (40.0) –
Daily dose, mg 5.7 ⫾ 2.66 4.9 ⫾ 1.75 3.7 ⫾ 0.82 5.1 ⫾ 2.59 0.485¶
MTX use
Yes, no. (%) 7 (38.9) 9 (47.4) 8 (40.0) 7 (35.0) –
Weekly dose, mg 12.9 ⫾ 3.93 10.5 ⫾ 2.67 9.7 ⫾ 3.12 12.1 ⫾ 2.67 0.006¶
HCQ use
Yes, no. (%) 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) –
Daily dose, mg – – 200.0# – –
Leflunomide use
Yes, no. (%) 10 (55.6) 6 (31.6) 8 (40.0) 10 (50.0) –
Daily dose, mg 20.0 ⫾ 0.00 20.0 ⫾ 0.00 20.0 ⫾ 0.00 19.0 ⫾ 3.16 0.510
Concomitant DMARD use, no. (%)
One DMARD 1 (5.6) 1 (5.3) 2 (10.0) 1 (5.0) –
Two DMARDs 15 (83.3) 16 (84.2) 14 (70.0) 17 (85.0) –
Three DMARDs 2 (11.1) 2 (10.5) 4 (20.0) 2 (10.0) –

* Except where indicated otherwise, values are the mean ⫾ SD. DAS28 ⫽ Disease Activity Score in 28 joints; CRP ⫽ C-reactive protein; ESR ⫽
erythrocyte sedimentation rate; RF ⫽ rheumatoid factor; HAQ DI ⫽ Health Assessment Questionnaire disability index (see Table 1 for other
definitions).
† P values are for overall comparison, and nonsignificance indicates randomization was done appropriately for demographic categories (age, sex,
etc.).
‡ By analysis of covariance (ANCOVA) with treatment and center as fixed factors.
§ By 2-sided Cochran-Mantel-Haenszel test adjusted for center (general association).
¶ By ANCOVA with treatment and center as fixed effects for continuous variables and by Cochran-Mantel-Haenszel test for categorical variables.
# Unable to estimate SD or SD not calculated.

LY2439821 group and the placebo group. If any analytic group
had fewer than 5 subjects, the 1-sided Fisher’s exact test was
used in place of the Cochran-Mantel-Haenszel test. No adjust-
ments for multiplicity were made. Pharmacokinetic parameters
were derived using a 2-compartment pharmacokinetic model
employing WinNonlin Professional, version 5.2 (Pharsight,
Mountain View, CA). Safety assessments were summarized
descriptively by treatment group.
In part A, 20 patients were considered sufficient to
determine safety and pharmacokinetics. In part B, completion
by 17 patients in each treatment group provided 80% power to
detect a treatment difference in the DAS28 of 1.2 at a
significance level of 0.05, using a 1-sided 2-sample t-test. This
assumed a common SD of 1.35 and did not include any
adjustments for multiplicity. Such power assumptions were
deemed appropriate for a first in-human proof-of-concept
study. For a 2-sided analysis, with all other assumptions as
above, 21 patients per group would have been required.
RESULTS
Patient baseline demographics, characteristics,
and disposition. Patients in part A were generally simi-
lar across treatment groups (Table 1). The only signifi-
cant differences in treatment groups occurred in disease
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 933

Table 3. Treatment-emergent adverse events by preferred term occurring in ⱖ2 patients from all LY2439821-treated groups combined (part A)
or in ⬎3% of patients from all LY2439821-treated groups combined (part B)*
LY2439821

All
LY2439821-treated
Preferred term Placebo 0.06 mg/kg 0.2 mg/kg 0.6 mg/kg 2.0 mg/kg groups
Part A
Diarrhea 0 (0.0) 1 (25.0) 1 (25.0) 1 (25.0) 1 (25.0) 4 (25.0)
Abdominal pain 0 (0.0) 0 (0.0) 2 (50.0) 0 (0.0) 0 (0.0) 2 (12.5)
Vomiting 0 (0.0) 1 (25.0) 0 (0.0) 0 (0.0) 1 (25.0) 2 (12.5)
Fatigue 0 (0.0) 0 (0.0) 0 (0.0) 2 (50.0) 0 (0.0) 2 (12.5)
Back pain 0 (0.0) 1 (25.0) 1 (25.0) 0 (0.0) 0 (0.0) 2 (12.5)
Headache 4 (100.0) 1 (25.0) 2 (50.0) 2 (50.0) 3 (75.0) 8 (50.0)
Paresthesia 0 (0.0) 1 (25.0) 1 (25.0) 0 (0.0) 0 (0.0) 2 (12.5)
Part B
Leukopenia 0 (0.0) – 1 (5.3) 1 (5.0) 2 (10.0) 4 (6.8)
Neutropenia 0 (0.0) – 1 (5.3) 1 (5.0) 0 (0.0) 2 (3.4)
Vertigo 0 (0.0) – 1 (5.3) 1 (5.0) 2 (10.0) 4 (6.8)
Pharyngitis 0 (0.0) – 1 (5.3) 1 (5.0) 1 (5.0) 3 (5.1)
Rhinitis 1 (5.6) – 0 (0.0) 3 (15.0) 0 (0.0) 3 (5.1)
Urinary tract infection 1 (5.6) – 1 (5.3) 1 (5.0) 1 (5.0) 3 (5.1)
Influenza 0 (0.0) – 1 (5.3) 1 (5.0) 0 (0.0) 2 (3.4)
Headache 1 (5.6) – 1 (5.3) 1 (5.0) 1 (5.0) 3 (5.1)
Hypotension 0 (0.0) – 1 (5.3) 1 (5.0) 0 (0.0) 2 (3.4)

* Values are the number (%) of patients experiencing an event. All adverse events listed were coded using the Medical Dictionary for Regulatory
Activities, version 10.0. In part A, there were 4 patients in the placebo-treated group and 4 patients in each of the LY2439821-treated groups, for
a total of 16 patients in all of the LY2439821-treated groups combined. In part B, there were 18 patients in the placebo-treated group, 19 patients
in the 0.2 mg/kg LY2439821-treated group, and 20 patients in each of the 0.6 mg/kg and 2.0 mg/kg LY2439821-treated groups, for a total of 59
patients in all of the LY2439821-treated groups combined.

duration and in HCQ and glucocorticoid use. For dis-
ease duration, the 0.06 mg/kg treatment group had RA
for an average of 22 years compared with an average of
5.6–8 years in all other groups. For HCQ use, the
placebo and the 0.2 mg/kg treatment groups had mean
daily doses of 300 mg and 200 mg, respectively (2 of 4
patients per group taking HCQ), while no patients in the
other treatment groups were taking HCQ. For glucocor-
ticoid use, the placebo and the 2.0 mg/kg groups had
mean daily doses of 50 mg and 0.5 mg, respectively,
compared with mean daily doses of 5–10 mg for the
other groups. In the placebo group, only 1 patient took
a concomitant glucocorticoid, at a dose of 25 mg twice a
day. Dose for concomitant glucocorticoid use was not
restricted as a criterion for entry into part A of the study.
In part B, there was a statistically significant difference
in the mean weekly dose of MTX; otherwise, patient
demographics and baseline characteristics were similar
across treatment groups (Table 2).
Part A enrolled 20 patients across 5 treatment
groups at 2 study centers in Australia. No patients
withdrew from part A due to adverse events (AEs); 2
patients withdrew for other causes (1 relocated and 1
withdrew based on investigator’s decision). Part B en-
rolled 77 patients across 4 treatment groups (5 subjects
from 3 study centers in Belgium and 72 subjects from 11
study centers in Romania). Study drug treatment was
discontinued for 3 patients due to AEs (1 patient in the
0.6 mg/kg group experienced worsening of arthritis; 2
patients in the 2.0 mg/kg group experienced moderate
leukopenia [white blood cell count ⬎2,200/␮l but
⬍3,000/␮l]). Treatment for 1 patient in the 2.0 mg/kg
group was discontinued due to an abnormal pretreat-
ment alanine aminotransferase concentration of 158
units/liter discovered after the first dose of study drug
had been administered.
Safety. AEs. Table 3 presents treatment-emergent
AEs occurring in ⱖ2 of the all-LY2439821–combined
patients in part A or in ⬎3% of the all-LY2439821–
combined patients in part B. The term “all-LY2439821–
combined patients” refers to the combined results from
all of the LY2439821-treated groups within either part A
or part B of the study.
In part A, headache was the most common
treatment-emergent AE and occurred most frequently
in the placebo group (Table 3). The most common
treatment-emergent AEs occurring in patients who re-
ceived LY2439821 were headache (8 patients compared
with all 4 placebo-treated patients, all of mild or mod-
erate intensity, and all resolved) and diarrhea (4 patients
934
compared with no placebo-treated patients, all of mild
or moderate intensity, and all resolved). There were no
serious AEs noted in part A.
In part B, the most common treatment-emergent
AEs that occurred in all-LY2439821–combined patients
were leukopenia and vertigo (4 patients for both, com-
pared with no placebo-treated patients for either), while
rhinitis was the most common treatment-emergent AE
occurring in any individual LY2439821 treatment group
(3 patients, all in the 0.6 mg/kg group, compared with 1
placebo-treated patient) (Table 3). There was no appar-
ent dose-response relationship in treatment-emergent
AEs. One serious AE occurred in the 0.6 mg/kg treat-
ment group. Three days after the last study drug infu-
sion, the patient reported a skin ulcer that had been
present for the previous 10 days. The patient was
hospitalized due to the skin ulcer 13 days after the last
dose of study drug. The ulcer improved with treatment,
and the investigator did not consider the event related to
study drug or protocol procedures.
Laboratory parameters. Evaluation of laboratory
parameters indicated that mean changes from baseline
were generally small and similar across treatment
groups, except for white blood cell, neutrophil, and
platelet counts, which were slightly but significantly
decreased in LY2439821-treated groups compared with
the placebo group at several times during the study.
Mild-to-moderate leukopenia and mild neutropenia
were reported as treatment-emergent AEs in 4 and 2
patients receiving LY2439821, respectively, compared
with none in the placebo-treated group (Medical Dictio-
nary for Regulatory Activities [MedDRA], version 10.0)
(Table 3). Based upon Common Terminology Criteria
for Adverse Events, version 3.0, 3 patients (all treated
with LY2439821) experienced white blood cell counts
⬍3,000/␮l during the study, and 5 patients (all treated
with LY2439821) experienced neutrophil counts
⬍1,500/␮l. There were no cases of thrombocytopenia
reported during the study.
Of the 3 patients with white blood cell counts
⬍3,000/␮l, one received 0.2 mg/kg LY2439821 and two
received 2.0 mg/kg LY2439821 (the lowest recorded
white blood cell count was 2,290/␮l at week 6). Both
patients in the 2.0 mg/kg treatment group were deemed
to have moderate intensity leukopenia possibly/probably
related to study treatment, and further study drug
treatment was discontinued for both patients (one after
3 doses of LY2439821; one after 4 doses of LY2439821).
Of the 5 patients with neutrophil counts
⬍1,500/␮l, two received 0.2 mg/kg LY2439821, two re-
GENOVESE ET AL
ceived 0.6 mg/kg LY2439821, and one received 2.0 mg/
kg LY2439821 (the lowest recorded neutrophil count
was 1,040/␮l at week 6). None of the patients discontin-
ued the study due to neutropenia.
Infections. The frequency of infections was low in
this study. Pharyngitis, rhinitis, urinary tract infections,
and influenza were the only infections reported in ⬎3%
of the all-LY2439821–combined patients in part B.
Rhinitis and urinary tract infections also occurred in the
placebo group; however, pharyngitis and influenza did
not. The most frequently occurring infection in any one
treatment group was rhinitis, which occurred in 3 pa-
tients taking 0.6 mg/kg LY2439821 (Table 3). Of the
patients with low white blood cell or neutrophil counts,
only 1 (with both mild leukopenia and mild neutropenia
as defined by MedDRA coding) had an infection (of the
urinary tract), which presented and resolved prior to the
onset of low white blood cell and neutrophil counts, as
well as a mild bacteriuria, determined by the investigator
to be possibly related to the study drug, which presented
after the onset of low white blood cell and neutrophil
counts.
Immunogenicity and allergic and infusion reac-
tions. Anti-LY2439821 antibodies were detected in 2
patients in part B of the study and at both postdosing
time points analyzed (week 8 and week 16). Antibodies
were detected in 1 patient each in the 0.2 mg/kg (titer of
1:2) and 0.6 mg/kg (titer of 1:10) treatment groups.
Neither of these patients experienced treatment-
emergent AEs, and no alterations in pharmacokinetics
were noted. No antibodies to LY2439821 were detected
in any placebo-treated patients.
One patient in part A (0.2 mg/kg treatment
group) experienced an adverse drug reaction, deemed by
the investigator to be a case of moderate immune type
III reaction. This patient experienced a skin rash and
generalized pruritus, preceded by various symptoms
(headache, abdominal pain, diarrhea, somnolence, and
anorexia) and followed by a delayed increase in trans-
aminases. All clinical symptoms resolved completely,
and there were no detectable anti-LY2439821 antibodies
in this patient. Another patient in the 0.2 mg/kg treat-
ment group in part A experienced infusion site pain.
There were no other reports of allergic or infusion
reactions during the study.
Pharmacokinetics. The pharmacokinetic proper-
ties of LY2439821 were similar in both parts of the
study. The mean terminal elimination half-life ranged
from 15 to 18 days in part A and from 14 to 16 days in
part B. Because of the long half-life, accumulation of
drug was observed in part B, in which dosing occurred
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 935

Figure 1. Change from baseline in Disease Activity Score in 28 joints (DAS28) by treatment over time, and percentage of patients meeting the
American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response). Values are
the least squares mean per treatment group. A, Change in DAS28 over time. B, ACR20 responses at week 10. The percentages of patients achieving
an ACR20 response were 73.7%, 70.0%, and 90.0% for the 0.2 mg/kg, 0.6 mg/kg, and 2.0 mg/kg LY2439821 (LY)–treated groups, respectively,
compared with 55.6% for the placebo-treated group (P ⱕ 0.05 versus placebo for the 2.0 mg/kg group). C, ACR50 responses at week 10. The
percentages of patients achieving an ACR50 response were 42.1%, 40.0%, and 35.0% for the 0.2 mg/kg, 0.6 mg/kg, and 2.0 mg/kg LY2439821-treated
groups, respectively, compared with 16.7% for the placebo-treated group. D, ACR70 responses at week 10. The percentages of patients achieving
an ACR70 response were 26.3%, 20.0%, and 25.0% for the 0.2 mg/kg, 0.6 mg/kg, and 2.0 mg/kg LY2439821-treated groups, respectively, compared
with 5.6% for the placebo-treated group. ⴱ ⫽ P ⱕ 0.05 versus placebo.

every 2 weeks. Maximum concentration and area under
the curve in both parts of the study showed dose
proportionality and linear pharmacokinetics across the
doses tested.
Efficacy. DAS28 scores. In part B, DAS28 scores
decreased as early as week 1 in all LY2439821 dose
groups relative to placebo, and this observation persisted
to the end of the study (Figure 1A). At week 10, the
changes from baseline in DAS28 values were ⫺2.3, ⫺2.2,
⫺2.4, and ⫺2.3 in the 0.2 mg/kg, 0.6 mg/kg, 2.0 mg/kg,
and all-LY2439821–combined groups, respectively
(P ⱕ 0.05 versus placebo for all except the 0.6 mg/kg
group), compared with ⫺1.7 in the placebo group
(least squares mean) (Figure 1A). At this time, 73.7%,
65.0%, 85.0%, and 74.6% of patients in the 0.2 mg/kg,
0.6 mg/kg, 2.0 mg/kg, and all-LY2439821–combined
groups, respectively, experienced improvements in the
DAS28 of ⱖ1.2 compared with 44.4% of placebo-treated
patients.
ACR20, ACR50, and ACR70 responses. Signifi-
cantly greater percentages of patients achieved an
ACR20 response at multiple time points and doses of
LY2439821. Significantly greater percentages of patients
achieved an ACR20 response at all dose levels by week
2 (26.3%, 30.0%, 45.0%, and 33.9% for 0.2 mg/kg,
0.6 mg/kg, 2.0 mg/kg, and all-LY2439821–combined
groups, respectively, compared with 0.0% for the pla-
cebo group) (Figure 1B). At week 10, the percentages of
patients achieving an ACR20 response were 73.7%,
70.0%, 90.0%, and 78.0% for the 0.2 mg/kg, 0.6 mg/kg,
2.0 mg/kg, and all-LY2439821–combined groups, respec-
tively (P ⱕ 0.05 versus placebo for the 2.0 mg/kg group),
compared with 55.6% for the placebo group. Also at
week 10, percentages of patients achieving ACR50 and
ACR70 responses in the LY2439821-treated groups (for
the ACR50 response, 42.1%, 40.0%, 35.0%, and 39.0%
for the 0.2 mg/kg, 0.6 mg/kg, 2.0 mg/kg, and all-
LY2439821–combined groups, respectively; for the
ACR70 response, 26.3%, 20.0%, 25.0%, and 23.7% for
the 0.2 mg/kg, 0.6 mg/kg, 2.0 mg/kg, and all-LY2439821–
combined groups, respectively) were higher than those
in the placebo group (16.7% and 5.6% for ACR50 and
ACR70 responses, respectively) (Figures 1C and D).
Throughout the study, most patients showed improve-
ments in the ACR core set of measures, with
LY2439821-treated patients showing significant im-
936
Figure 2. Responses in American College of Rheumatology core set parameters by treatment over time. A, Swollen joint counts. B, Tender joint
counts. C, Health Assessment Questionnaire disability index (HAQ DI) score. D, Change from baseline in C-reactive protein. Values are the least
squares mean per treatment group. ⴱ ⫽ P ⱕ 0.05 versus placebo. LY ⫽ LY2439821.
provements compared with placebo-treated patients at
multiple time points (Figures 2 and 3).
DISCUSSION
IL-17 is a unique proinflammatory cytokine ame-
nable to targeting inflammatory and autoimmune dis-
eases. This phase I, two-part, single/multiple dose ad-
ministration study in patients with active RA provides
preliminary insight into the safety and potential efficacy
of targeting this novel pathway. With currently available
disease-modifying therapies, less than two-thirds of RA
patients reach at least an ACR50 response. Further-
more, disease remission (DAS28 ⬍2.6) is achieved by
only a small minority of these patients, emphasizing the
need to develop novel therapies. The results of this study
demonstrate that neutralization of IL-17 could provide a
viable goal for future treatment of RA. IL-17 acts as an
“effector” cytokine, much like TNF␣. IL-17 can syner-
gize with other proinflammatory cytokines to stimulate
release of additional proinflammatory cytokines and
chemokines, nitric oxide, and matrix metalloproteinases
in many cell types. Since the IL-17 receptor is ubiqui-
tously expressed, virtually all cell types have been dem-
onstrated to have a biologic response to IL-17. Evidence
GENOVESE ET AL
suggests that IL-17 may have several roles including the
promotion of neutrophil homeostasis, host defense
against extracellular bacteria and some fungi, and
chronic pathogenic inflammation such as that found in
autoimmune disease, asthma/allergy, and lung inflam-
mation (11). There is considerable evidence that IL-17
plays an important and nonredundant role in the patho-
genesis of arthritis in animal models (21).
The two-staged design of this trial allowed the
assessment of pharmacokinetics and tolerability with
single dose administration in RA patients receiving
concomitant DMARD therapy without requiring a par-
ticular level of active disease to be present. Upon
satisfactory completion of part A, and with no clear
concerns about tolerability, the study continued with a
parallel design in part B, which explored multiple dose
administration and allowed both safety and efficacy
assessments in a population of patients with active RA
receiving concomitant oral DMARD therapy.
Pharmacokinetic parameters were reproducible
across both parts of the study. The half-life was similar
after single and multiple dosing, ranging from 15 to 18
days and from 14 to 16 days, respectively, indicating the
potential for dosing every 2 weeks or less frequently.
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA
Figure 3. Responses in American College of Rheumatology core set
parameters by treatment over time. A, Patient’s assessment of pain.
B, Patient’s global assessment of disease activity. C, Physician’s global
assessment of disease activity. Values are the least squares mean per
treatment group. ⴱ ⫽ P ⱕ 0.05 versus placebo. LY ⫽ LY2439821.
937
Tolerability appeared to be favorable, with only 1 seri-
ous AE reported in part B of the study. AEs were also
few, mild to moderate in severity, and did not increase
with drug dose escalation. White blood cell, platelet, and
neutrophil counts were slightly but significantly de-
creased in LY2439821 treatment groups versus the
placebo group at several time points during the study.
Four patients experienced mild-to-moderate leukope-
nia, only 2 patients experienced mild neutropenia ac-
cording to MedDRA, version 10.0 coding (Table 3), and
no patients experienced thrombocytopenia. Given the
low incidence of patients with leukopenia or neutrope-
nia, and the dosing with concomitant medications known
to be associated with decreased blood cell counts, the
causal relationship of these changes to LY2439821 is
unclear. However, IL-17 induces production of granulo-
cyte colony-stimulating factor and other chemokines and
cytokines, contributing to neutrophil progenitor differ-
entiation and maturation (14). Therefore, blocking such
effects with LY2439821 could possibly result in reduced
neutrophil counts.
Because the study was an initial assessment of
LY2439821 in humans, the focus on safety was conser-
vative, and the patients experiencing moderate leukope-
nia were withdrawn due to the potential higher risk of
infection. In a relatively short experimental period,
patients treated with LY2439821 demonstrated robust
and significant improvements in DAS28 scores as well as
significantly greater percentages of ACR20 responses.
Both parameters showed improvements that occurred
early in the study (as early as week 1) and that were
sustained through at least 16 weeks (8 weeks after the
last dose of drug). LY2439821-treated patients also
showed significant improvements at multiple time points
in tender joint count, swollen joint count, patient’s
assessment of pain, patient’s global assessment of dis-
ease activity, and HAQ DI score. The physician’s global
assessment of disease activity decreased in LY2439821-
treated patients but with fewer significant differences
versus placebo than observed for the patient’s global
assessment of disease activity.
Since this was a phase I study, there was a
primary focus on safety and tolerability after both single
and multiple dose administration; thus, efficacy para-
meters were not addressed until part B. Further, despite
the observed efficacy, the study failed to demonstrate a
clear dose-response relationship between LY2439821
and efficacy parameters or with respect to tolerability.
The 2.0 mg/kg dose, however, did show consistent im-
provements compared with the other dose levels, and
938
findings were not meaningfully different with regard to
safety. A high placebo response (55.6% of placebo-
treated patients had an ACR20 response at weeks 10
and 16) was observed in this study. It is not clear whether
this observation represents unique features of this study,
the patient population, the investigators, or access to
care in the populations concerned. Despite the placebo
response, a significant difference was demonstrated be-
tween the active treatment and placebo groups in both
the DAS28 and the percentages of ACR responders.
The DAS28 at week 10 was chosen as the primary
efficacy end point because, as a validated continuous
outcome measure and a frequently used composite index
in RA outside of the US, it allowed for a comparison of
efficacy with the smaller sample size consistent with
phase I safety studies. Furthermore, the study was not
powered to draw definitive conclusions on dose effects
or to assess accurately the proportion of ACR respond-
ers, but rather to provide an early opportunity to assess
potential benefit in a multiple dose phase I trial.
Recently, results were presented from a proof-of-
concept trial evaluating another anti–IL-17 antibody
(26). Patients in that study also had active disease
despite taking concomitant MTX. The data indicated
that treatment with anti–IL-17 improved signs and
symptoms compared with placebo, further validating this
cytokine as a potentially valuable target for the treat-
ment of RA.
The results of the current study indicate that
LY2439821 may offer a therapeutic alternative for pa-
tients with active RA. The ultimate safety and efficacy
profile of this approach will need to be further explored
in large scale clinical trials. The positive results ob-
served, coupled with a good tolerability profile, provide
a solid proof of concept for LY2439821 in the treatment
of RA. The utility of this compound in RA therefore
warrants further investigation.
ACKNOWLEDGMENTS
We wish to thank the patients and the principal
investigators for this study, and to acknowledge all of the
enrollment contributions by investigators, who were as follows:
Dr. Peter Ryan, Dr. Susan Proudman, Dr. Iuliana Mirela
Biagini, Dr. Silvia Bojin, Dr. Monica Sanziana Capraru, Dr.
Liana Maria Chicea, Dr. Dorica Cristei, Dr. Eugen Dumitru,
Dr. Ruxandra Ionescu, Dr. Mihail Bogdan Jantes, Dr. Gavrila
Mirea, Dr. Gabriela Udrea, Dr. Eugenia Mociran, Dr. Ilse
Hoffman, Dr. Jan Lenaerts, and Dr. Filip Van Den Bosch. We
wish to acknowledge Ling Liu, PhD, and Jirong Lu, PhD, for
their contributions to the functional and physical characteriza-
tion of LY2439821; and Susan Strobel, PhD, Stephen L.
Myers, MD, John Polzer, PhD, Kristy Kikly, PhD, Pierre-Yves
GENOVESE ET AL
Berclaz, MD, Eiry Roberts, MD, and Olivier Benichou, MD,
for their contributions in the preparation of the manuscript.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Genovese had full access to all of
the data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
Study conception and design. Genovese, Roberson, Sloan-Lancaster.
Acquisition of data. Van den Bosch, Roberson, Bojin, Biagini, Ryan.
Analysis and interpretation of data. Genovese, Sloan-Lancaster.
ROLE OF THE STUDY SPONSOR
As sponsor of the study, Chorus, a Division of Eli Lilly, was
responsible for the creation of the study design, in close collaboration
with Dr. Genovese. Chorus oversaw the data collection and analysis, as
well as data interpretation. Chorus actively participated in the writing
of the manuscript. Eli Lilly approved the content of the submitted
manuscript prior to its submission for publication. Publication of the
manuscript was contingent on Eli Lilly having an opportunity to review
it prior to its submission.
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